Reflecting the advent of the so-called "high-age" society, it has become a serious public concern to develop medical measures for treatment of senile dementia as caused by damages or disturbances of the cerebral functions which are, in turn, attributable to cerebrovascular diseases or damages or disturbances of intracerebral energy metabolism. A variety of drugs has heretofore been developed as anti-dementia drugs. At the present time, senile dementia, amnesia as caused by cerebrovascular diseases and the biological mechanisms of occurrence of these disorders or diseases have not yet been elucidated fully. In these circumstances, no sufficient clue has yet been established to discover and screen effective cerebral drugs. As experimental methods for inducing amnesia in normal mammalian animals, it is known to administer such an agent which inhibits the in vivo synthesis of nucleic acids or proteins, or an anticholinergic agent. Amnesia is also known to be inducible by cerebral anoxia, ischemic load or the like. With using such model animals which have amnesia induced by these causative agents, it has been attempted to detect and develop cerebral drugs which are capable of amelioractively treating or preventing the amnesia. In addition, when using such model animals which have cerebral anoxia induced either by giving a lethal dose of potassium cyanide or by subjecting to hypobaric or normabaric hypoxic conditions, namely, the reduced oxygen-supply conditions, attempts have also been made to develop cerebral drugs which are effective for the improvement or amelioration of cerebral circulation metabolism or intracerebral energy metabolism. These matters are related to e.g. in "Folia Pharmacol. Japan", 85, 323-328 (1985); ibid., 86, 445-456 (1986): and Japanese Patent Application first publication "Kokai" No. 117468/79 or its corresponding U.S. Pat. No. 4,369,139.
It is well accepted that oxygen deprivation is one of the most damaging conditions affecting the animal or human brain, and that when oxygen supply tot he brain becomes deficient, cerebral functions cease after brief periods of cerebral anoxia and tissue destruction ensues. Consequently, any suitable agents which enable the brain to withstand even mild degrees of cerebral anoxia would be expected to be useful as a cerebral protective agent or a drug for improving or ameliorating the damaged or disturbed cerebral functions of the brain (the drug of this utility is hereinafter sometimes merely called "a cerebral drug"). Many compounds have been investigated for their cerebral protective effect on cerebral anoxia which is experimentally induced by subjecting the animal to hypoxic conditions, whereby there is obtained a suggestion or indication that the tested compounds are effective for treatment of cerebral anoxic or ischemic diseases or disorders (see, e.g. "Arch. int. Pharmacodyn."233, 136-144 (1978) and "Life Science" 13, 467-474 (1973)).
However, the cerebral drugs which have been provided so far can hardly be said to have fully satisfactory effects and proven reliability. Under these circumstances, there remains a demand for the development of new cerebral drugs which are still stronger and safer than the known drugs as provided to date.
On the other hand, Japanese Patent Application first publication "Kokai" No. 24823/79 discloses a process for the preparation of N,N-di-substituted glycol amides which have the utility as stabilizers or solvents for polymers. It is described there that N,N-di-substituted oxamic acids are formed as by-products in said process. Specific compounds whose formation as the by-products were confirmed in the process of the above patent publication are limited to N,N-dimethyloxamic acid, N,N-diethyloxamic acid, N,N-di-n-propyloxamic acid, N,N-di-n-butyloxamic acid, N,N-di-allyloxamic acid, N,N-cyclopentyloxamic acid, N-methyl-N-phenyloxamic acid and N,N-diphenyloxamic acid. The above patent publication discloses neither utility of these N,N-di-substituted oxamic acids nor their physiological activities. Further, N,N-di-isopropyloxamic acid is disclosed in the "Journal of Organometallic Chemistry" 297, 379-390 (1985) but its physiological activities are not reported at all there.
An object of this invention is to prepare and provide novel compounds having excellent pharmacological effects for the improvement of the damaged or disturbed cerebral functions of the brain as well as a high level of safety and being free of side effects. Another object of this invention is to provide novel cerebral drugs. To achieve these objects, we, the present inventors, have proceeded with extensive investigations. As a result, we have now found that compounds having anti-anoxia effects, in other words, cerebral protective effect against cerebral anoxia, are useful or promising as drugs having medicinal effects capable of treating cerebration disorders of mammals, including human, when such compounds are effective in significantly prolonging the survival time of mice having cerebral anoxia experimentally induced under hypobaric hypoxia conditions in the experiments wherein the cerebral anoxia mice are used as model animals. We, the present inventors, have thus been interested in some N,N-dialkyloxamic acids (which may also be called N,N-dialkyloxaminic acids) which are disclosed in Japanese Patent Application first publication "Kokai" no. 24823/79, and we have tested the cerebral protective effect of these known compounds against cerebral anoxia. Moreover, we have also synthesized novel N,N-di-substituted oxamic acid compounds which had not been reported in any prior art publications, and we have assayed the cerebral protective effect of these novel compounds against cerebral anoxia.
As a result of our above investigations and tests, we have found that N,N-di-substituted oxamic acid compounds which include a class of novel oxamic acid compounds having the below-described formula (Ia) and which may generally be represented by the below-described formula (I) have the cerebral protective effect against cerebral anoxia and low toxicity. Their potential usefulness as the cerebral drugs has also been ascertained.
In addition, we have also succeeded in providing a process which can advantageously produce the novel compounds of the formula (Ia) on a commercial scale.